title: Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling.
abstract: Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity for colorectal and other cancers, but toxicity from COX inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their tumor cell growth inhibitory activity does not require COX inhibition, although the underlying mechanism is poorly understood. Here, we report that the NSAID sulindac sulfide inhibits cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP-dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of colon tumor cells. Sulindac sulfide did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors tadalafil and sildenafil also selectively inhibited the growth of colon tumor cells that expressed high levels of PDE5 compared with colonocytes. The mechanism by which sulindac sulfide and the cGMP/PKG pathway inhibits colon tumor cell growth involves the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin T-cell factor transcriptional activity, leading to downregulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP-degrading isozymes.
authors.affiliation: Corresponding Author: Gary A. Piazza, Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Suite 3029, Mobile, AL 36604. gpiazza@usouthal.edu.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Xi
authors.forename: Heather N
authors.initials: HN
authors.lastname: Tinsley
authors.forename: Evrim
authors.initials: E
authors.lastname: Gurpinar
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Gary
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Yonghe
authors.initials: Y
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Adam B
authors.initials: AB
authors.lastname: Keeton
authors.forename: Ashraf H
authors.initials: AH
authors.lastname: Abadi
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moyer
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chang
authors.forename: Margie L
authors.initials: ML
authors.lastname: Clapper
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
mesh_terms: D000970:Antineoplastic Agents / Q000032:analysis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D002243:Carbolines / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology; D000077022:Survivin; D000068581:Tadalafil; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C530104:CCND1 protein, human; D002243:Carbolines; D051034:Inhibitor of Apoptosis Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000077022:Survivin; D019938:Cyclin D1; D013467:Sulindac; C025462:sulindac sulfide; D000068581:Tadalafil; D000068677:Sildenafil Citrate; D017869:Cyclic GMP-Dependent Protein Kinases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP